Cocaine is a reinforcing drug with high abuse liability, morbidity and mortality. Cocaine is the second most commonly used illicit drug (following marijuana) in the United States. According to the 2003 National Survey on Drug Use and Health, more than 34 million Americans (14.7%) age 12 or older had used cocaine at least once in their lifetime. Effective medication for the treatment of cocaine overdose and addiction is a major unmet need of worldwide importance. Our laboratory has studied the relationship between the long-term effects of chronic cocaine abuse and the regional neuroadaptive changes that occur in human brain. Through our collaboration with the Miami-Dade County Medical Examiner Department, we have developed a bank of postmortem brain specimens from cocaine abusers and age, gender and ethnicity matched control subjects. We also have developed a collection of postmortem brain specimens from victims of cocaine-related excited delirium. Medical examiners nationwide are increasingly citing this condition when suspects die in police custody. We have demonstrated that alpha synuclein, a protein implicated in neurodegenerative disorders, such as Parkinson's disease, may play a role in the development and maintenance of cocaine addiction. Alpha synuclein is an important regulator of the DA system. The protein interacts with the DA transporter, and regulates DA content, neurotransmission and synaptic strength of DA neurons. We propose here integrated molecular approaches to continue our studies to characterize counteradaptations in alpha synuclein, dopamine presynaptic markers and catecholamine metabolism (DA, DOPAC, HVA) in postmortem human brain from chronic cocaine abusers. Together, these studies will provide a molecular and circuit-based accounting of coordinated dysregulation of alpha synuclein and presynaptic markers of the DA system in cocaine dependence. Alpha synuclein dysregulation in DA neurons may be one of the neurobiological factors that produce vulnerability to addiction and relapse in individuals with a history of cocaine dependence. Agents that modulate SNCA expression are under development for the treatment of Parkinson's disease and may be an alternative therapeutic option for normalizing DA homeostasis in cocaine dependence.